Drug interactions with voltage-dependent K + channels and N-methyl-D-aspartate (NMDA) receptor coupled-cation channels were studied in cultured hippocampal neurons and in fibroblasts transfected with K + channel genes using whole-cell voltage-clamp and single channel recording techniques. The aim of this work was to explore new strategies for the rational development of antiepileptic drugs based upon their interaction with neuronal ion channel systems. Work was focused in four areas: (1) kinetic analysis of NMDA antagonism by novel dissociative-anesthetic-like anticonvulsant drugs; (2) tetrahydroaminoacridine (THA) block of NMDA-activated cation channels; (3) mechanism of action of K + channel activator drugs; and (4) drug effects on K + channel currents carried by molecularly defined K + channel proteins in fibroblast cells transfected with K + channel genes. The novel anticonvulsants phenylcyclohexylamine (PCA) and 5-aminocarbonyl-5H-dibenzo[a,d]cyclohepten -5,10-imine (ADCl) are structurally related to the dissociative anesthetics phencyclidine and MK-801. However, unlike their parents which cause motor toxicity at low doses, PCA and ADCl protect against seizures in animal models at doses that fail to cause motor impairment. We have determined that the more favorable toxicity profile of PCA and ADCl may relate to their ability to block NMDA responses more rapidly than do PCP and MK-801. Tetrahydroaminoacridine (THA), a centrally active cholinesterase inhibitor that may provide symptomatic benefit in Alzheimer's disease, was found to produce a voltage-dependent block of NMDA responses in cultured hippocampal neurons and also to reduce the frequency and duration of NMDA evoked single channel currents in outside-out membrane patches. The antihypertensive cromakalim has been previously found to activate a K + current in cultured hippocampal neurons. We have demonstrated that metabolic inhibitors can activate a similar K + current. We have also obtained evidence for the existence of ATP-sensitive K + channels in hippocampal neurons, and our data indicate that cromakalim and metabolic inhibitors can activate these channels. These channels may play a role in protecting central neurons from brain ischemia. Drugs like cromakalim that activate K + channels in CNS neurons have potential as anticonvulsants, and perhaps also in the treatment of brain ischemia. The effects of various K + channel blockers and activators are being studied on K + channels expressed in fibroblast cells transfected with K + channel genes. We observed that the NGK1 K + channel is insensitive to tetraethylammonium, but is effectively blocked by 4-aminopyridine, PCP, and histrionicotoxin, an alkaloid from frog skin.